Iopanoic Acid Research Articles

Thyroxine 5'-deiodinase activity in pineal gland and frontal cortex: nighttime increase and the effect of either continuous light exposure or superior cervical ganglionectomy.

Type II T4 5'-deiodinase (5'-D) activity was studied in pineal gland, frontal cortex, and anterior pituitary of male rats. Enzymatic activity was determined by the release of 125I using [3',5'-125I]T4 as substrate. Daytime levels of 5'-D activity were maximal for anterior pituitary (346.2 +/- 142.5 fmol 125I released/mg protein.h), followed by pineal gland (61.5 +/- 8.7 fmol 125I released/mg protein.h) and frontal cortex (3.1 +/- 0.5 fmol 125I released/mg protein.h). Twenty-four-hour fluctuations of 5'-D activity were apparent in the pineal gland and cortex. For pineal, peak 5'-D activity (43.4 +/- 11.4 fmol 125I released/gland.h) occurred at 0100 h, with values at this time being 8-fold greater than basal daytime levels. Superior cervical ganglionectomy (SCGX) or exposure to continuous light (LL) completely abolished the nocturnal rise of 5'-D activity. Treatment with iopanoic acid also inhibited 5'-D activity in pineal (32.1 +/- 3.5 vs. 18.8 +/- 1.7 fmol 125I released/gland.h) without influencing either the N-acetyltransferase activity or the melatonin content. In cortex, peak 5'-D activity occurred at 0500 h (5.3 +/- 0.4 fmol 125I released/mg protein.h), with values at this time being 1.5-fold greater than basal daytime levels. SCGX moderately depressed enzymatic activity, while LL exposure strikingly enhanced the nocturnal increase (11.7 +/- 1.1 vs. 19.3 +/- 2.4 fmol 125I released/mg protein.h at 0300 h). 5'-D activity exhibited no 24-h fluctuation in the anterior pituitary gland, and neither SCGX nor LL exposure affected enzyme levels in this tissue. Our data demonstrate the existence of a 24-h rhythm of type II T4 5'-D activity in pineal gland and cortex, with peak levels occurring at night; in pineal, the sympathetic neural input is indispensable for the rhythm, since SCGX prevented it. In cortex, the apparent paradoxical effect of LL and SCGX on 5'-D activity indicates that other mechanisms are involved in its regulation.

Long term treatment of Graves' disease with iopanoic acid (Telepaque).

To investigate the long term utility of the cholecystographic contrast agent iopanoic acid (Telepaque) for treatment of Graves' hyperthyroidism, we studied 40 patients treated with 500 mg, orally, daily for 1-12 months. We measured thyroid size; body weight; serum T3, T4, and free T4 concentrations; and antithyroglobulin and antimicrosomal antibody levels at monthly intervals. Based on the effects of the therapy, the patients were divided into 3 groups: 6 patients had excellent responses with return of serum thyroid hormone levels to normal (group A); 12 patients had fair responses, but 1 thyroid hormone test remained elevated (group B); and 22 patients had minimal benefit (group C) with only slight clinical improvement and transient reduction of serum T3 concentration. Mean serum T3 levels decreased significantly after 1 month of therapy in all 3 groups and became normal in groups A and B, but the reduction in group C was not sustained. Mean serum T4 and free T4 levels remained above normal during the course of therapy in groups B and C. Sixty-eight percent of patients in group C had large goiters compared with 33% of group A and 25% of group B, and those in group C tended to have more severe biochemical hyperthyroidism initially. There were no significant changes in antibody titers during therapy. These data indicate that iopanoic acid is not effective therapy for many hyperthyroid patients.

Optimal response of key enzymes and uncoupling protein to cold in BAT depends on local T3 generation.

We have examined the activity of three lipogenic enzymes [malic enzyme (ME), glucose-6-phosphate dehydrogenase (G-6-PD), and acetyl coenzyme A (CoA) carboxylase], the activity of the mitochondrial FAD-dependent alpha-glycerolphosphate dehydrogenase (alpha-GPD), and the mitochondrial concentration of uncoupling protein (UCP) in brown adipose tissue (BAT) of euthyroid and hypothyroid rats, both at room temperature and in response to acute cold stress. These enzymes and UCP are important for the thermogenic response of BAT in adaptation to cold. The basal level of the lipogenic enzymes was normal or slightly elevated in hypothyroid rats maintained at 23 degrees C, but the levels of alpha-GPD and UCP were markedly reduced. Forty-eight hours at 4 degrees C resulted in an increase in the activity of G-6-PD, acetyl-CoA carboxylase, and alpha-GPD and in the concentration of UCP both in euthyroid and hypothyroid animals, but the levels reached were invariably less in hypothyroid animals, indicating that thyroid hormone is necessary for a full metabolic response of BAT under maximal demands. Of all variables measured, the most affected was UCP (only one-fifth of the response of euthyroid rats to cold) followed by alpha-GPD (approximately 50% the euthyroid response). The administration of replacement doses of triiodothyronine (T3) to hypothyroid rats for 5-7 days did not normalize any of the BAT responses, whereas the replacement of thyroxine (T4) for only 2 days sufficed to normalize them all. This effect of T4 was abolished by preventing its conversion to T3 with iopanoic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of type-II thyroxine 5′-deiodinase activity in rat Harderian gland

Thyroxine 5′-deiodinase activity was studied in male rat Harderian gland homogenates. The reaction rate was proportional to the tissue content in the homogenate and dependent on pH, with an optimum pH of 7.0, and temperature, between 4–37°C. 5′-deiodinase activity was increased by dithiothreitol (DTT) in a dose-dependent manner, and inhibited moderately by propylthiouacil (PTU) and strongly by iopanoic acid (lA). Thyroidectomy enhanced the enzymatic activity (30-fold above the control value) but this increase is totally prevented by the in vivo iopanoic acid treatment. Thyroxine 5′-deiodinase activity was also dependent on T4 concentration (Km = 3.3 nM ; Vmax = 10 fmol 1251-released/mg protein/h) and exhibited a nyctohemeral rhythmicity with a maximal activity at 03.00h (4-fold above basal values) and minimal activity between 12.00–21.00 h.

Inhibition of the response of thyrotrophin to thyrotrophin-releasing hormone by thyroxine in hypothyroid rats treated with iopanoic acid: evidence suggesting an intrinsic biological activity of thyroxine without prior conversion to 3,5,3'-tri-iodothyronine.

The effects of a physiological replacement dose of thyroxine (T4) on the response of plasma TSH to TRH in hypothyroid rats were studied. Animals were treated with iopanoic acid (IOP; 5 mg/100 g body weight) or vehicle 24, 12 and 1.5 h before the experiment. Thereafter, 800 ng T4/100 g body weight were administered i.v. and 20 min later 1 microgram TRH/100 g body weight was injected i.v. In control rats the basal concentration of TSH was 1450 +/- 300 (S.E.M.) mu./1. The plasma concentration of TSH 10 min after injection of TRH increased to 167 +/- 14% of the mean basal value (P less than 0.001). The injection of T4 significantly (P less than 0.005) reduced the TSH response to TRH in both IOP-treated (118 +/- 15%) and vehicle-treated (108 +/- 15%) rats compared with untreated controls. Tri-iodothyronine (T3) was undetectable in the plasma of all rats, whereas the plasma concentration of T4 was 121 +/- 19 nmol/l in IOP-treated and 139 +/- 23 nmol/l in vehicle-treated rats 30 min after injection of 800 ng T4/100 g body weight. In pituitary cells of control rats, cytoplasmic radioactivity 30 min after injection of [125I]T4 was 1.28 +/- 0.13 X 10(-2)% (76 +/- 6% T4 and 17 +/- 3% T3), whereas that in nuclei reached 0.42 +/- 0.36 X 10(-2)% (51 +/- 4% T4 and 28 +/- 3% T3) of the injected dose.(ABSTRACT TRUNCATED AT 250 WORDS)

PHARMACOKINETICS OF T3 AND T4 AFTER ACUTE THYRDXINE OVERDOSE: EFFECT OF PTU AND IOPANOCIC ACID

Over a 1 yr period, 15 ingestions of thyroxine in children under 5 yrs of age were evaluated. All patients had initial serum T4 levels determined within 7 hrs of ingestion. Multiple T3 and T4 serum levels were determined in 7 patients. Peak T4 levels ranged from 16-118 mog/dl with 3 patients >75 mog/dl. The estimated peak T4 level occurred <12 hrs in 71% of the patients; the estimated peak T3 level occurred >20 hrs in 71% of the patients. In 5 patients who received no specific treatment, the mean serum T4 t1/2 was 2.84 da (range 1.7-4.54 da) and the mean serum T3 t1/2 was 5.1 da (range 1.9-12.3 da). Specific therapy to inhibit conversion of T4 to T3 was given in 2 patients during which serum t1/2 were: We conclude that in acute pediatrio overdose of thyroxine: (1) peak T4 levels occur earlier than peak T3 levels, (2) in untreated patients the t1/2 of T4 is shorter than T3, and (3) shortly after administration, PTU and iopanoic acid can prolong T4 t1/2 and shorten T3 t1/2.

Iododerma Occurring After Orally Administered Iopanoic Acid

A 45-year-old man with multiple myeloma developed iododerma after oral cholecystography with iopanoic acid. The lesions appeared two days after two exposures to iopanoic acid given within one week. To our knowledge, this is the first reported case of iododerma in association with multiple myeloma and orally ingested radiocontrast dye.

Effects of iopanoic acid on thyroid hormone receptor, growth hormone production, and triiodothyronine generation from thyroxine in pituitary GH1 cells.

We have studied the effect of iopanoic acid (IOP), a radiographic contrast agent which inhibits T4 to T3 conversion, on thyroid hormone nuclear receptors, GH response to T4 and T3, and T4 5'-monodeiodination in GH1 cells, a rat pituitary cell line. IOP at concentrations higher than 10 microM inhibits iodothyronine binding to the nuclear receptor without changing the dissociation constant (Kd) (0.1 nM for T3 and 1 nM for T4), and reduces the GH response to 50 nM T4, 5 nM T3, or the combined effect of T4 and glucocorticoids. These results could be explained by an inhibition of protein synthesis which was reduced by more than 50% by 50 microM IOP. By contrast, nontoxic concentrations of IOP did not change the GH response to different doses of T4 ranging from 1 nM to 50 nM. We also examined T3 generation from T4 and found that the intracellular T3 levels of cells incubated with 50 nM T4 were almost as high as those of cells incubated with 5 nM T3 which induces a full GH response. Intracellular T3 levels were markedly reduced in the cells incubated with T4 and IOP, but GH production was not reduced despite these differences in T3 levels. Additionally, more than 40% of the nuclear receptor was occupied by T3 in cells incubated with T4, whereas more than 90% was occupied by T4 in cells receiving the same amount of T4 with 5 microM IOP. Our results suggest that the effect of T4 on GH production by GH1 cells could be attributed to an important extent to the T3 generated from it, whereas when T4 monodeiodination is strongly inhibited, most of the biological activity is a result of intrinsic T4 activity.

Iododerma occurring after orally administered iopanoic acid

Iododerma occurring after orally administered iopanoic acid

The effect of iopanoic acid on thyrotropin secretion in patients with cirrhosis of the liver.

Ten patients with liver cirrhosis and six normal subjects were studied to evaluate the effect of iopanoic acid (IA) on thyrotropin secretion. A thyrotropin-releasing-hormone (TRH) test was performed before and 5 days after IA administration (single oral dose of 3 g). After IA administration, a significant increase in TSH response to TRH was observed in normal subjects. In cirrhotics, however, it did not significantly increase after IA administration. The serum T3 and T3/TBG ratio were significantly decreased and the serum T4 and T4/TBG ratio were increased after IA administration in normal subjects and cirrhotics. There was no significant difference in the % decrease in serum T3, % increase in serum T4 or other thyroid hormone parameters including TSH in IA induced TSH responders (R) and non-responders (NR). However, r-T3 before and after IA in R was higher than those in NR. The values for hepatic function tests such as serum albumin, prothrombin time, 45 minutes retention rate of bromsulphalein (BSP 45 min) and the cholinesterase (ChE) level in R were not different from those of NR. These results suggested that in cirrhotics, abnormal regulation of the hypothalamo-pituitary system might exist.

In-vitro conversion of thyroxine to tri-iodothyronine by chicken hepatic 5'-deiodinase: kinetic studies.

In-vitro studies with chicken liver homogenates demonstrate that the conversion of thyroxine (T4) to tri-iodothyronine (T3) is dependent upon tissue concentration, time of incubation, pH, temperature, the presence of dithiothreitol (DTT) and the concentration of substrate (T4), and is heat-labile. The generation of T3 is inhibited by iopanoic acid and 6-n-propyl-2-thiouracil. The kinetics of conversion of T4 to T3, determined by Lineweaver-Burke analysis, indicated an apparent Michaelis-Menten constant (Km) of 1.16 mumol/l with a maximum velocity (Vmax) of 44.57 pmol T3 generated/mg protein per min from T4. Dithiothreitol appears to behave as a co-substrate for this system with an apparent Km of 98.5 mumol/l and a Vmax of 1.41 pmol T3 generated/mg protein per min at a T4 concentration of 5 mumol/l. These data suggest that the conversion of T4 to T3 in fowl proceeds by means of an enzymatic system, probably 5'-monodeiodinase, and is responsible for maintaining T3 levels in vivo.

The effects of amiodarone on the electrocardiogram of the guinea-pig are not explained by interaction with thyroid hormone metabolism alone.

The iodine-containing contrast medium iopanoic acid induces alterations of thyroid hormone metabolism comparable to those observed with the iodine-containing antiarrhythmic drug amiodarone. Both compounds inhibit the intracellular conversion of thyroxine (T4) to triiodothyronine (T3). Using iopanoic acid, the question was investigated, in guinea-pigs, whether inhibition of T4----T3 conversion is by itself associated with the same changes in the electrocardiogram, i.e. QT prolongation and bradycardia, as those observed during amiodarone treatment. At a dose of 4 g kg-1, iopanoic acid induced maximal inhibition of the T4----T3 conversion. Although these changes were even more pronounced than those in a control group of animals treated with 2.12 g amiodarone kg-1, neither prolongation of the QT nor a slowing of the heart rate was observed. QT prolongation and bradycardia were induced only by amiodarone treatment but not by iopanoic acid. Iopanoic acid at the high toxic dose of 12 g kg-1 induced the same degree of inhibition of T4----T3 conversion as the 4 g kg-1 dose. QT prolongation and slowing of the heart rate were apparent at this dose in parallel with a loss of weight. It is concluded that even a maximal inhibition of the T4----T3 conversion has no effect on the ECG of guinea-pigs. The inhibition of the T4----T3 conversion alone does not explain the QT prolongation and bradycardia observed with amiodarone treatment. The amiodarone effects on the ECG may represent a combination of interactions with thyroid hormones and antiadrenergic activity.

Investigations on iodothyronine deiodinase activity in the maturing rat brain.

5-Monodeiodination of T4 and T3 and 5'-monodeiodination of T4 and rT3 were studied in brain homogenates of male Sprague-Dawley rats, aged 1-60 days. Portions of the homogenates were incubated with the substrates at 37 C for 30 min. The reaction products were estimated by specific RIAs. All of the four reactions were dependent upon time, temperature, pH, and upon the concentrations of substrate, thiol, and tissue protein. Maximal reactions were obtained between 40 and 160 mM dithioerythritol. T4 5'-deiodination proceeded optimally at pH 7.4 and 0.4 microM substrate, the other reactions at pH 8.5 and 10 microM substrate. The four reactions were inactivated by heat (56 C, 30 min) and inhibited by 10(-5) M iopanoic acid. Only rT3 5'-deiodination was inhibited by 3 X 10(-4) M propylthiouracil (greater than 95%). In cerebellum, basal ganglia, brainstem, and hypothalamus both T4 and T3 5-deiodinase activity were very high in perinatal rats [up to 5.56 pmol/(min X mg protein) in hypothalamus], and decreased rapidly with age. In cortex and olfactory bulb these enzyme activities were low after birth, followed by an increase during the growth spurt [up to 632 fmol/(min X mg protein) in olfactory bulb]. T4 and rT3 5'-deiodinase activity in all brain regions studied were at their lowest in perinatal rats. During and after the growth spurt an increase was observed [up to 457 fmol/(min X mg protein) in cerebellum]. The reciprocal course of 5- and 5'-deiodination between birth and growth spurt in most of the brain regions studied might lead to a reduced intracellular thyromimetic activity during the perinatal period.

Avian hepatic t 3 generation by 5'-monodeiodination: Characterization of two enzymatic pathways and the effects of goitrogens

1. 1. The enzymatic nature of 5'-monodeiodination (5'-D) in avian liver homogenates was demonstrated by abolishment of activity by iopanoic acid (IOP). 2. 2. T 3 production from T 4 was dependent on enzyme and substrate concentrations, incubation time, incubation temperature, and pH. 3. 3. Two pathways of 5'-D activity were present in avian liver and exhibited characteristics similar to those described in mammalian tissues. 4. 4. Type II activity was identified as propylthiouracil (PTU)-insensitive activity. Type I (PTU-sensitive) was determined by difference between Total and Type II. 5. 5. K m values were 1.58 μM T 4 for Total activity and 0.90 nM T 4 for Type II, corresponding to the characteristics of the mammalian pathways. 6. 6. The effects of goitrogens on avian hepatic 5'-D were equivalent to those reported for the mammalian enzyme.

Radioiodination via isotope exchange in pivalic acid

A variety of benzoic and aryl aliphatic mono and polyiodinated acids and esters (sterol, triglyceride) were radioiodinated in 55–99% radiochemical yield by isotope exchange with Na 125I in a melt of pivalic acid. In general, the reaction was complete in 1 h at 155°C with little or no substrate decompostion. High specific activity studies afforded 125I-labeled iopanoic acid with a specific activity of over 700 Ci/mmol.

Subcellular Localization of Thyroxine 5′-Deiodinase Activity in Bovine Anterior Pituitary*

Bovine anterior pituitary glands were fractionated by differential centrifugation. T4 5'-monodeiodination to T3 was found predominantly in microsomal fractions (M2; 105,000 . g pellet) enriched in glucose-6-phosphatase and 5'-nucleotidase activities. T4 5'-deiodinase activity in M2 fraction was 85.2 fmol T3/min X mg protein and represented an 8.5-fold enrichment over homogenate specific activity (10.6 fmol T3/min . mg protein). Further subcellular localization of the T4 5'-deiodinase was effected by discontinuous sucrose density gradient centrifugation. Maximum T4 5'-deiodinase activity was found in fraction P5 at the interface of densities 1.18/1.20 (200 fmol T3/min . mg protein) and correlated with the profile of glucose-6-phosphatase and not with that of 5'-nucleotidase, the maximum activity of which was recovered in fraction P1 at the interface of densities 1.03/1.12. Electron microscopic examination of the fractions confirmed that P5 contained in excess of 90% rough membranes in contrast to 10% or less in P1. Characterization of T4 5'-deiodinase activity was carried out in M2 preparations. The reaction was thiol dependent, requiring the presence of 50 mM dithiothreitol or more (Km, 38 mM), with a maximum velocity of 55-150 fmol T3/min . mg protein (n = 8). Enzyme activity was substrate dependent, with a Km for T4 between 35-70 nM. 5'-Monodeiodination of T4 was abolished by heating to 70 C for 30 min and was unaffected by EDTA. Propylthiouracil and methimazole did not inhibit T3 generation. Iopanoic acid, on the other hand, was a competitive inhibitor of the 5'-monodeiodination reaction, abolishing T3 production in a dose-dependent manner with a Ki of 3 microM. These data indicate that the bovine anterior pituitary contains significant T4 5'-deiodinase activity, which shares many properties of the type II 5'-deiodinase of the rat. Bovine anterior pituitary T4 5'-deiodinase appears to be predominantly localized in the rough endoplasmic reticulum.

Inhibitory Effect of Iopanoic Acid on the Thyrotropin Stimulated Release of Cyclic Adenosine 3′,5′-Monophosphate and of 3,5,3′-Triiodothyronine from Perifused Rat Thyroids

Using a perifusion system, we studied the effect of iopanoic acid, an iodinated contrast agent used in oral cholecystography, on the release of cAMP, T3, T4, and rT3 from perifused rat thyroid pieces. A 0.1 mg/ml iopanoic acid solution significantly inhibited the TSH-stimulated release of cAMP (without iopanoic acid, 8175 +/- 373; with iopanoic acid, 5169 +/- 355 fmol/mg thyroid X 3 h, mean +/- SE) and T3 (without iopanoic acid, 971 +/- 32; with iopanoic acid, 659 +/- 32 pg/mg thyroid X 3 h) in the presence of 3-isobutyl-1-methylxanthine. T4 and rT3 releases were not significantly affected. Inhibition of TSH-stimulated T3 release by iopanoic acid was also observed at a concentration of 0.01 mg/ml. Propylthiouracil completely abolished the inhibitory effect of iopanoic acid on TSH-stimulated cAMP release but not on TSH-stimulated T3 release. TSH-stimulated cAMP release was augmented by iodide at a concentration of 1 X 10(-3) M in the presence of 3-isobutyl-1-methylxanthine but suppressed by iodide at a concentration of 1 X 10(-5) M. TSH-stimulated T3 release was suppressed slightly at both concentrations of iodide. These results suggest that iopanoic acid may have an inhibitory effect on the TSH-stimulated cAMP and T3 release from perifused rat thyroids. This effect can probably be attributed to the iodide contained in the agent and to the inhibited intrathyroidal conversion of T4 to T3.

Characteristics of thyroxine 5'-deiodination in cultured human placental cells. Regulation by iodothyronines.

Human and rat placental homogenates convert L-thyroxine (T4) to 3,5,3'-L-triiodothyronine (T3) via a pathway termed type II iodothyronine deiodination. To study regulation of this pathway, cell dispersions were prepared from human placental chorionic-decidual membrane. Dispersed cells deiodinated T4 and 3,3',5'-triiodothyronine (rT3), but not T3, at the 5' position. The reaction was only slightly inhibited by 1 mM 6-n-propylthiouracil, enhanced by dithiothreitol, and substantially inhibited by 50 nM iopanoic acid. Incubation of the cells in thyroid hormone-depleted medium induced a near doubling of T4 5'-deiodination in 36-48 h, with a significant rise seen as early as 12 h. Addition of T4, rT3, or T3 to hormone-depleted medium impaired the rise in type II deiodination in a dose-dependent fashion. T4 and rT3 were equipotent in this regard, and T3 was 2-3 times less potent. T4 was effective in physiological concentrations, 6.5-13 nM in medium containing 10% calf serum, and the effect of T4 was not due to its conversion to either T3 or rT3. In cells with deiodinase activity raised by 48 h incubation in thyroid hormone-depleted medium, addition of T4, T3, or rT3 reversed the increase in 8-24 h. Secretion of prolactin and beta hCG by the dispersed cells was not substantially affected by thyroid hormone deprivation. The increase in type II deiodination during thyroid hormone deprivation appears to depend on a signal from the thyroxine molecule, per se, and could potentially defend intracellular, and/or circulating, T3 pools in pathological states of mild-to-moderate hypothyroxinemia.

Modulatory effect of thyroid hormones on uptake of phosphate and other solutes across luminal brush border membrane of kidney cortex.

The mechanism whereby thyroid hormones modulate the transport properties of luminal brush border membrane (BBM) of renal proximal tubules was studied in thyroparathyroidectomized rats. Administration of both T4 and T3 increased BBM capacity for Na+ gradient-dependent uptake of phosphate (Pi) by BBM vesicles (BBMV). This effect of thyroid hormones was present in thyroparathyroidectomized and hypophysectomized rats, and it was not blocked by a saturating dose of propranolol. The stimulatory effect of T3 and T4 on BBM transport of Pi was dose dependent in the range of 5.2-520 nmol/100 g BW. Pretreatment of rats with inhibitors of 5'-monodeiodinase (5'-DI), iopanoic acid or ipodate, prevented the increase in serum T3 in rats injected with T4, but it did not diminish the increase in BBM transport of Pi. Administration of iopanoic acid and ipodate also prevented a 5-fold increase in 5'-DI activity in renal cortical tissue elicited by T4 administration. Treatment with T3 resulted in an increase of Pi transport across BBM from kidneys of rats subjected to dietary Pi deprivation due either to total fasting or to feeding of a low Pi diet. Further, T3 administration enhanced amiloride-sensitive Na+-H+ countertransport across BBM, but the uptake of 22Na+ by BBMV in the absence of pH gradient was not changed. The Na+ gradient-dependent uptake of L-[3H]proline by BBMV was slightly decreased, but the uptake of [14C]citrate was not changed in response to T3. Administration of T3 increased Pi transport in BBMV prepared from juxtamedullary cortex, but not in BBMV from superficial cortex. Conversely, the rate of Na+-H+ countertransport was enhanced, and the enzymatic activity of alkaline phosphatase was decreased in BBMV from superficial cortex; no changes in these parameters were found in BBMV from juxtamedullary cortex. Our results indicate that the stimulatory effect of administered T3 and/or T4 on renal BBM transport of Pi is distinct from the modulatory effect of dietary Pi intake and is not secondary to the beta-effect of catecholamines or to altered secretion of GH. Both T3 and T4 elicit the increase in BBM transport of Pi in a similar manner; T4 is effective even after profound inhibition of in vivo conversion of T4 to T3 by potent 5'-DI inhibitors. Administration of T3 stimulates Na+ gradient-dependent Pi uptake only in BBMV prepared from the juxtamedullary zone, and it stimulates the H+-Na+ countertransport only in BBMV from the outer cortical zone. These findings indicate that thyroid hormones modulate the two distinct transport functions of BBM derived from two different populations of renal proximal tubules.

Effect of peripheral thyroid hormone metabolism on cardiac arrhythmias

The recent development of specific radioimmunoassays for thyroxine (T4), triiodothyronine (T3) and reverse triiodothyronine (rT3) has allowed the study of the peripheral metabolism of thyroid hormones. 1–2 Two unrelated drugs, amiodarone and iopanoic acid, 3,4 divert the peripheral metabolism of T4 from the production of T3 to the production of rT3, a metabolically inactive compound. The relation between the remarkable antiarrhythmic effects of amiodarone and its effects on peripheral thyroid metabolism are unclear. Although the antiarrhythmic action of amiodarone parallels the increase of rT3, 5 a cause and effect relation has not been clearly defined. Iopanoic acid, in contrast, a totally unrelated compound with no known antiarrhythmic effect and used for oral cholescystography, affects the peripheral thyroid hormone metabolism in a manner similar to that of amiodarone. 4 The purpose of this report was to assess the effect of treatment with iopanoic acid in patients with ventricular arrhythmias and to test indirectly whether the blockade of the peripheral metabolism of T4 to T3 could be efficacious in treating ventricular arrhythmias in humans.